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15th February 2012 @ 00:02

Resolution of MNR26-1 with (-)-dibenzoyl-L-tartaric acid (MNR6-1)to obtain R-di-methoxy-PZQamine (MNR27-1)

* Using the crude MNR26-1 to see if it can be cleaned up durin gthe resolving step.

Hazard and Risk Assessment: As for MNR2-1

MNR26-1 (3.5 g, 13.34 mmol) and (-)-dibenzoyl-L-tartaric acid. 2IPA(6.38 g, 13.34 mmol) was dissolved in a mixture of isopropanol (58 mL) and water (12 mL) - The reagents went into solution with minimal heating and after standing in the freezer overnight no crystals appeared. The reaction mixture was concentrated and taken up in IPA (20 mL) and water (10 mL) with heating, allowed to cool to room temperature and left in the freezer overnight. The solution had frozen by the time it was taken out of the freezer. Toluene was added (40 mL) and as doing so what looked like a white precipitate appeared. The mixture was heated to reflux to get everything back into solution and allowed to cool to room temperature then in an ice bath for 1 hour. At this point there was still difficulty getting nice crystals to form. The mixture was concentrated again and taken up in a mixture of IPA/water/EtOAc/Hexane/toluene (I know!) at which point a precipitate formed in the cocktail. This was filtered under vacuum to give a light brown solid (14.24 g!)

A small portion of this was disolved in water and taken to pH 12 by the addition of NaOH (5 M) solution then extracted with DCM (10 mL x 4), dried, filtered and concentrated.

Test recrystallisations were attempted on small amounts of the crude solid recovered.

8:2 IPA/Water 9:1 IPA/Water 8:2 Acetone/Water 9:1 Toluene/MeOH 1:1 IPA/Hexane - This was the only one to form nice white crystals after 4 hours.

The crystals from the 1:1 IPA/Hexane recrystallisation were filtered and washed with hexane then disolved in water and taken to pH 12 by the addition of NaOH (5 M) solution then extracted with DCM (5 mL x 4), dried, filtered and concentrated to give only a few mgs of amine. Chiral HPLC showed what looked like a single enantiomer.

The remainder of the solid was dissolved in 1:1 IPA/Hexane (200 mL) and left to stand over the weekend. Very little crystallised out so the mixture was concentrated and filtered to give a pale brown solid (2.364 g). This was then dissolved in 1:1 IPA/Hexane (50 mL) and left to stand overnight. A solid had crashed out but not the white crystals as before, again just a pale brown solid (0.718 g)

20 mg of this solid was dissolved in water and taken to pH 12 by the addition of NaOH (5 M) solution then extracted with DCM (5 mL x 4), dried, filtered and concentrated to give a white solid (5 mg). Chiral HPLC showed what looked like only one enantiomer.

The rest of the solid (0.698 g) was dissolved in water and taken to pH 12 by the addition of NaOH (5 M) solution then extracted with DCM (5 mL x 4), dried, filtered and concentrated to give a white solid (0.286 g). Chiral HPLC showed only one peak and was confirmed by making a piked sample using MNR26-1.

Very poor yield but this included a lot of filtration steps and a lot of material was discarded as it was impure. Probably didn't help tha tthe starting material wasn't clean.

Note - the other test reactions MNR27-2 - MNR27-8 were carried out at the same time as all this was going on.

mnr26-1 15EtOH 05mL_140312.pdf

mnr27-1_recrystal3_spike 15MeOH 05ml.pdf

mnr27-1_recrystal3_spike 15MeOH 05ml.pdf

NMR Data

mnr27-1-rxstal3.pdf

mnr27-1-rxstal3_13C.pdf

 

LRMS 

5f R LRMS MNR27-1 dont include.jpg

HRMS 

5f R HRMS MNR27-1.jpg

IR 

5f R IR MNR27-1.jpg
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Attached Files
MNR27-1 scheme.png
MNR27-salt.png
mnr27-1 table.PNG
mnr27-1.jpg
mnr27-1_recrystal3 15MeOH 05ml.pdf
mnr27-1_recrystal3_spike 15MeOH 05ml.pdf
mnr26-1 15EtOH 05mL_140312.pdf
mnr27-1_recrystal3_spike 15MeOH 05ml.pdf
mnr27-1-rxstal3.pdf
mnr27-1-rxstal3_13C.pdf
5f R HRMS MNR27-1.jpg
5f R IR MNR27-1.jpg
5f R LRMS MNR27-1 dont include.jpg